Detection of drug-resistant tuberculosis (DR-TB) increases each year in South Africa (SA). Most cases result from airborne transmission of already resistant TB strains. Epidemic control relies on rapid diagnosis and initiation of effective treatment to reduce the period of infectiousness and ongoing transmission. The rapid diagnostic test, Xpert MTB/RIF, has replaced smear microscopy for routine screening of all cases of presumptive TB in SA. Xpert also detects rifampicin (RIF) resistance, an indicator of more extensive drug resistance, allowing rapid initiation of effective second-line treatment. Definitive diagnosis of DR-TB relies on laboratory confirmation of MTB, along with drug-susceptibility testing (DST) using culture-based (phenotypic) and/or molecular (genotypic) techniques. A standardised treatment regimen, consisting of five (or six) drugs (pyrazinamide, (ethambutol), kanamycin, moxifloxacin, ethionamide, terizidone), is offered to individuals following initial diagnosis of RIF resistance. Treatment regimens are individualised if and when molecular mutation details and second-line DST results indicate more extensive second-line drug resistance. DR-TB treatment outcomes are poor owing to death, and interruption and failure of current treatment. Reliable access to newer, more effective drugs within shorter, more tolerable regimens is desperately needed to improve the chance of a cure for DR-TB patients.